Protein tyrosine kinases (PTKs) play an integral role in the development of T cells. Mutations or the absence of a number of cytoplasmic PTKs result a variety of immunodeficiencies. One such PTK is the zeta-chain associated PTK, ZAP-70. Studies in both humans and mice demonstrate the central importance of ZAP-70 in T cell development and T cell development function. Absence of human ZAP-70 is associated with an autosomal recessive form of severe combined immunodeficiency. These patients develop no CD8+ peripheral T cells and have normal numbers of nonfunctional CD4+ T cells. Mice lacking the ZAP-70 gene lack both CD4+ and CD8+ peripheral T cells. Moreover, zap-70 is also required for the appropriate selection and development of T cells. While these initial studies demonstrate the central importance of ZAP-70 in thymocyte development and appropriate selection of the TCR repertoire, the mechanism(s) by which ZAP-70 can mediate these vastly diverse biological responses remain unclear. An understanding of how ZAP-70 functions in thymocyte development will provide a paradigm for PTKs in immune cell development and may provide insights into differences in the developmental requirements of CD4+ and CD8+ T cells. Moreover, these studies may provide additional mechanistic information for therapeutic interventions in drug design for T cell lymphomas, immunodeficiencies, autoimmune diseases, and transplantation rejection.